Gene expression in normal and doxorubicin-impaired wounds: importance of transforming growth factor-beta

The function of transforming growth factor-beta (TGF-beta) in vivo remains unknown despite the fact that it has been identified in numerous biologic processes involving the regulation of cell growth including tissue repair. Doxorubicin is a potent antitumor drug that has been shown to have detrimental effects on wound healing. With specific complementary DNA probes for TFG-beta and type 1 collagen, RNA from wounds of rats treated with saline solution and doxorubicin was analyzed for the expression of each gene at different times after wounding. In a second study, either 2 micrograms exogenous TGF-beta or vehicle was added to wounds of rats treated with doxorubicin, and wound RNA was analyzed in a similar manner. In wounds from rats treated with saline solution, messenger RNA (mRNA) for TGF-beta peaks on day 7 after wounding and is also elevated on days 3 and 10; mRNA for collagen is elevated on days 7 and 10. Doxorubicin decreases mRNA for TGF-beta and collagen on each day. Topical application of TGF-beta to wounds of rats treated with doxorubicin increases collagen mRNA levels to normal or supranormal levels. This study suggests that the impaired healing induced by doxorubicin may be a result of decreased gene expression for TGF-beta and that topical replacement of this growth factor may correct the defect.